1. Field of the Invention
The present invention relates to the treatment of fatty deposits in atherosclerotic blood vessels. In particular, the invention relates to the prevention or inhibition of arterial plaque by administering a green porphyrin compound. Unlike standard photodynamic protocols, no purposeful irradiation with light is needed to effect the desired inhibition.
2. Description of the Related Art
Atherosclerosis is an arterial disease in which fatty substances (lipids) accumulate in the intima or inner media, the innermost membranes encompassing the lumen of the artery. The resulting lesions are referred to as atherosclerotic plaque. Clinical symptoms finally occur because the growing mass of the atherosclerotic plaque gradually reduces blood flow through the involved artery, thereby compromising the tissue or organ function distal to it. Atherosclerosis and its complications, such as myocardial infarction, stroke, and peripheral vascular diseases, remain major causes of morbidity and mortality in the Western World. Coronary heart disease alone has been reported to account for over half a million deaths in the United States annually.
The fundamental lesion of atherosclerosis is the atheromatous or fibrofatty plaque, which causes narrowing of the artery, predisposes to thrombosis, calcifies, leads to weakening of the muscle, and causes aneurysmal dilation. Atherosclerotic plaques are approximately rounded, raised lesions, usually off-white to white in color superficially, and perhaps a centimeter in diameter. The center of larger plaques may exude a yellow, grumous fluid. A typical cellular plaque is shown in FIG. 3 and consists of:
1. a fibrous cap composed mostly of smooth muscle cells with a few leukocytes and relatively dense connective tissue, which contains elastin, collagen fibrils, proteoglycans, and basement membrane; PA1 2. a cellular area beneath and to the side of the cap consisting of a mixture of macrophages, smooth muscle cells, and T lymphocytes; and PA1 3. a deeper "necrotic core" containing cellular debris, extracellular lipid droplets, and cholesterol crystals. PA1 a. administering to a subject an amount of a green porphyrin compound effective to prevent or inhibit said development; and PA1 b. allowing said inhibition to occur in the absence of irradiation with light absorbed by said green porphyrin. PA1 a. an amount of a green porphyrin compound effective to prevent or inhibit said development when administered to a subject in need of such treatment, even in the absence of irradiation with light absorbed by said Gp; and PA1 b. a pharmaceutically acceptable excipient.
Munro et al., "Biology of Disease; The Pathogenesis of Atherosclerosis: Atherogenesis and Inflammation", Laboratory Investigation 58:3, 249-50 (1988).
Left unchecked, the formation of plaque can result in the complete occlusion of the artery and severe clinical consequences. For example, when complicated, the lesion becomes a calcified fibrous plaque containing various degrees of necrosis, thrombosis and ulceration. With increasing necrosis and accumulation of cell debris, the arterial wall progressively weakens, and rupture of the intima can occur, causing aneurysm and hemorrhage. Arterial emboli can form when fragments of plaque dislodge into the lumen. Stenosis and impaired organ function result from gradual occlusion as plaques thicken and thrombi form.
The treatment of atherosclerosis generally focuses on the care of patients suffering from atherosclerotic complications and typically follows one of four basic approaches: (1) the diseased vascular segments may be replaced with prosthetic or natural grafts, going as far as whole heart transplantation; (2) drugs, such as antiarrhythmic agents, anticoagulants and plasma lipid lowering agents, may be administered to enable the patient to live with the conditions; (3) the plaque may be physically reduced in size by the use of a balloon catheter in angioplasty; or (4) photodynamic therapy may be used which couples the administration of photosensitive agent and subsequent irradiation with light to excite the photosensitizer, thus producing a cytotoxic effect. Spears, U.S. Pat. No. 4,512,762, issued Apr. 23, 1985 and U.S. Pat. No. 4,566,636 issues Mar. 25, 1986.
In photodynamic therapy, the photosensitizers used are capable of localizing in malignant cells, either by natural tendency or because they have been intentionally targeted to a specific type of tissue, or both. When irradiated, they may be capable of fluorescing and, thus, may be useful in diagnostic methods related to detecting target tissue. However, even more importantly, the photosensitizer has the capacity, when irradiated with light at a wavelength which the compound absorbs, of causing a cytotoxic effect against whatever cells or other tissue in which the photosensitizer has localized. Although not yet definitively established, it is thought that this cytotoxic effect is due to the formation of singlet oxygen upon irradiation.
In most photodynamic therapy protocols, a method must be found for the irradiating light to reach the targeted tissue where the photosensitizer has been localized. This is particularly difficult when the wavelength of irradiation that is required to activate the compound is in the range of about 630 nm, a wavelength that is readily absorbed by natural chromophores in blood and other surrounding tissues. In one technique, the patient must be catheterized with a light-emitting catheter being inserted into the diseased artery or other vessel so that the light-emitting portion of the catheter is adjacent to the atherosclerotic plaque. For example, a light-emitting balloon catheter may be used to displace light-opaque blood between the external balloon surface and the atherosclerotic plaque by inflation of the balloon. Alternatively, a form of "liquid light" may be injected into the vascular tree such that the "liquid light", which mixes freely with blood or a blood replacement, perfuses the diseased artery. Spears, U.S. Pat. No. 4,512,762.
In another method, to keep dosages low and decrease the patient's sensitization to light, a preferred group of "green porphyrins" have made it possible to conduct photodynamic therapy with light having a wavelength range outside of that normally strongly absorbed by the blood or other normal tissues, specifically around 670-780 nm. In addition to providing an effective in vivo treatment at lower concentrations and reducing hypersensitivity of non-target tissues, a greater depth of penetration by the irradiating light is also usually achieved. Because these photosensitizers appear green in color rather than red, they have been nicknamed "green porphyrins." It is known that green porphyrins can be used to detect and treat atherosclerotic plaques in a photodynamic therapy protocol. See, for example, Levy et al., U.S. Pat. No. 5,399,583 issued Mar. 21, 1995 (column 2, lines 14-15); Levy et al., U.S. Pat. No. 4,920,143 issued Apr. 24, 1990 (column 10, lines 58-59); Levy et al., U.S. Pat. No. 5,095,030 issued Mar. 10, 1992 (column 2, lines 8-9 and column 15, lines 29-30); and Levy et al., U.S. Pat. No. 5,171,749 issued Dec. 15, 1992 (column 2, lines 12-13 and column 18, lines 1-4 and 35-47).
It has also been found that green porphyrins can exert certain "dark effects", which take place without any purposeful irradiation at all with photoactivating light. For example, it has been found that administration of a green porphyrin following a vascular intervention procedure, such as angioplasty, can significantly reduce the proliferation of smooth muscle cells that typically builds up in the intima to cause "restenosis" or "intimal hyperplasia". See Vincent et al., U.S. Pat. No. 5,422,362 issued Jun. 6, 1995. Moreover, it has been found that the immune response to a specific antigen may be modulated and that the intercellular communication that results in thrombosis or blood clot formation in the bloodstream by may be interfered with by administering green porphyrins in the absence of light, as described in co-pending application Ser. No. 08/374,158 filed Jan. 13, 1995.
However, until now, the use of green porphyrins to treat fatty atherosclerotic plaques has been limited to a photodynamic therapy protocol, which requires that the administration of the photosensitizer be followed by the irradiation of the inner membrane of the blood vessel with light having a wavelength capable of stimulating the green porphyrin to produce a cytotoxic effect. It would thus be advantageous to provide a treatment to inhibit or prevent arterial plaque that would completely avoid the necessity for specialized light-emitting devices. It has now been discovered that green porphyrins may be used to prevent or inhibit the development of arterial plaque without having purposeful light exposure of any kind.